Chemoenzymatic synthesis and synthetic application of enantiopure aminocyclopentenols: Total synthesis of carbocyclic (+)-uracil polyoxin C and its α-epimer

Article abstract of DOI:10.1021/jo0496796

Carbocyclic uracil polyoxin C (+)-2 and its α-epimer (-)-3 were synthesized in an efficient fashion from cis-4-(N-tert-butylcarbamoyl)cyclopent- 2-en-1-ol (±)-7. The synthesis incorporates a concise, inexpensive chemoenzymatic synthesis of enantiopure ami

Full text of DOI:10.1021/jo0496796

Ch em oen zym a tic Syn th esis a n d Syn th etic
Ap p lica tion of En a n tiop u r e
Am in ocyclop en ten ols: Tota l Syn th esis of
Ca r bocyclic (+)-Ur a cil P olyoxin C a n d Its
r-Ep im er
Fangzheng Li, J ohn B. Brogan, J ennifer L. Gage,
Deyi Zhang, and Marvin J . Miller*
Department of Chemistry and Biochemistry, University of
Notre Dame, Notre Dame, Indiana 46556
mmiller1@nd.edu
Received February 25, 2004
F IGURE 1. Structures of aristeromycin, neplanocin A, and
uracil polyoxin C, 1.
Abstr a ct: Carbocyclic uracil polyoxin C (+)-2 and its
R-epimer (-)-3 were synthesized in an efficient fashion from
cis-4-(N-tert-butylcarbamoyl)cyclopent-2-en-1-ol (()-7. The
synthesis incorporates a concise, inexpensive chemoenzy-
matic synthesis of enantiopure aminocyclopentenols, a Pd-
(0)-catalyzed substitution reaction, and a mild reduction of
an R-nitro ester by TiCl3/sodium borohydride. Significantly,
this process demonstrates the synthetic utility of the ver-
satile enantiopure aminocyclopentenol building block (-)-
4.
synthase, thereby preventing fungal cell wall growth. As
this enzyme is found only in fungi and some insects, these
agents tend to be nontoxic to plants and mammals. The
modest activity exhibited by the polyoxins and nikkomy-
cins against human pathogens such as C. albicans may
be due to their poor outer membrane transport and/or
hydrolytic instability.7 The latter suggests that improved
activity might be observed through isosteric replacement
of the furanyl oxygen with a methylene group.
An impressive array of chemical8 and chemoenzymatic9
methods have been reported for the synthesis of carbocy-
clic nucleosides. Among these, cyclopentadiene-derived
hetero- Diels-Alder cycloadducts9g,10 such as 5 (Scheme
1) have emerged as particularly useful intermediates. A
Prompted by naturally occurring carbocyclic nucleo-
sides such as aristeromycin1a and neplanocin A1b (Figure
1), an impressive variety of unnatural carbocyclic nucleo-
sides have been prepared in recent years that display
intriguing biological activities.2 In addition to their
demonstrated utility as antiviral3 and antitumor4 agents,
these compounds promise improved metabolic stability
and decreased toxicity relative to their natural nucleoside
counterparts.5 Although considerable attention has been
paid to derivatives such as AZT and carbovir,6 which
contain a 5′-hydroxymethyl substituent, comparatively
little effort has been directed toward the synthesis of
carbocyclic analogues of nucleosides containing an amino
acid substituent at the 5′ position such as uracil polyoxin
C, 1 (Figure 1).7
(8) For a recent review, see: Crimmins, M. T. Tetrahedron 1998,
54, 9229. For recent reports, see: (a) Santana, L.; Teijeira, M.; Uriarte,
J . J . Heterocycl. Chem. 1999, 36, 293. (b) Shi, J . X.; McAtee, J . J .; Wirtz,
S. S.; Tharnish, P.; J uodawlkis, A.; Liotta, D. C.; Schinazi, R. F. J .
Med. Chem. 1999, 42, 859. (c) Comin, M. J .; Rodriguez, J . B. An. Quim.
Arg. 1998, 86, 131. (d) Singh, J .; Bisacchi, G. S.; Ahmad, S.; Godfrey,
J . D.; Kissick, T. P.; Mitt, T.; Kocy, O.; Vu, T.; Papaioannou, C. G.;
Wong, M. K.; Heikes, J . E.; Zahler, R.; Mueller, R. H. Org. Proc. Res
Dev. 2 1998, 6, 393. (e) Demaison, C.; Hourioux, C.; Roingeard, P.;
Agrofoglio, L. A. Tetrahedron Lett. 1998, 39, 9175. (f) Wang, P. Y.;
Schinazi, R. F.; Chu, C. K. Bioorg. Med. Chem. Lett. 1998, 13, 1585.
(g) Blanco, J . M.; Caamano, O.; Fernandez, F.; Garcia-Mera, X.; Lopez,
C.; Rodriguez, G.; Rodriguez-Borges, J . E.; Rodriguez-Hergueta, A.
Tetrahedron Lett. 1998, 39, 5663. (h) Shuto, S.; Niizuma, S.; Matsuda,
A. J . Org. Chem. 1998, 13, 4489. (i) Nieto, M. I.; Blanco, J . M.;
Caamano, O.; Fernandez, F.; Gomez, G. Tetrahedron 1998, 54, 7819.
(j) Ahn, S. K.; Kim, D.; Son, H. J .; J eong, B. S.; Hong, R. K.; Kim, B.
Y.; Kim, E. N.; Chung, K. H.; Kim, J . W. Chem. Commun. 1998, 9,
967. (k) Balo, C.; Blanco, J . M.; Fernandez, F.; Lens, E.; Lopez, C.
Tetrahedron 1998, 54, 2833. (l) Toyota, A.; Kaneko, C. J . Synth. Org.
Chem. J pn. 1998, 2, 107. (m) Kapeller, H.; Marschner, C.; Weissen-
bacher, M.; Griengl, H. Tetrahedron 1998, 54, 1439.
(9) Recent reports: (a) Katagiri, N.; Yamaguchi, M.; Kaneko, C.
Heterocycles 1998, 5, 1023. (b) Matsumoto, K.; Kaneko, M.; Katsura,
H.; Hayashi, N.; Uchida, T.; Acheson, R. M. Heterocycles 1998, 2, 1135.
(c) Yoshida, N.; Kamikubo, T.; Ogasawara, K. Tetrahedron Lett. 1998,
39, 4677. (d) Mulvihill, M. J .; Gage, J . L.; Miller, M. J . J . Org. Chem.
1945, 10, 3357. (e) Kato, K.; Suzuki, H.; Tanaka, H.; Miyasaka, T.
Tetrahedron: Asymmetry 1998, 6, 911. (f) Roberts, S. M.; Williamson,
N. M. Curr. Org. Chem. 1997, 1, 1. (g) Olivo, H. F.; Yu, J . X. J . Chem.
Soc., Perkins Trans. 1 1998, 3, 391. (h) Mulvihill, M. J .; Miller, M. J .
Tetrahedron 1998, 54, 6605.
The polyoxins and closely related nikkomycins exhibit
selective antifungal activity through inhibition of chitin
* To whom correspondence should be addressed. Tel: (574) 631 7571.
Fax: (574) 631-7571.
(1) (a) Quinkert, G., Ed. Synform 1989, 7, 192. (b) Quinkert, G.,
Ed. Synform 1989, 7, 225.
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(b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S. R.;
Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (c) Mansour, T.
S.; Storer, R. Curr. Pharm. Res. 1997, 3, 227. (d) Marquez, V. E. In
Advances in Antiviral Drug Design; DeClercq, E., Ed.; J AI Press Inc.;
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10.1021/jo0496796 CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/25/2004
4538
J . Org. Chem. 2004, 69, 4538-4540

SCHEME 2
F IGURE 2. Target molecules.
SCHEME 1
SCHEME 3
report from Cowart and co-workers11 regarding the use
of cycloadduct 5 for this purpose prompted us to disclose
our most recent findings related to asymmetric syntheses
of carbocyclic nucleosides from racemic 5. We here report
an efficient chemoenzymatic synthesis that provides the
versatile synthetic intermediate (-)-4 in 98% ee and in
only two steps from racemic cycloadduct (()-5. As part
of an ongoing project, the utility of (-)-4 was then dem-
onstrated through the total synthesis of carbocyclic uracil
polyoxin C (+)-2 and its R-epimer (-)-3 (Figure 2).
We previously reported application of cycloadduct (()-5
for the synthesis of racemic carbocyclic uracil polyoxin
C (()-2.12 The success of our kinetic enzymatic resolution
of aminocyclopentenols13a indicated (+)-2 could now be
readily prepared through unification of the two methods.
In the process of completing this synthesis, substantial
improvement over the existing methodology was realized
including identification of a novel protocol for N-O reduc-
was discovered that use of commercially available im-
mobilized C. antartica B enzyme resulted in dramatic
improvement in substrate selectivity. Using this im-
mobilized enzyme, the desired acetate (-)-4 was obtained
with 92-98% ee after 43% conversion, and this protocol
worked well on a tens of grams scale. In addition to the
outstanding efficiency observed using this new protocol,
the resin-bound enzyme could be easily recovered from
the reaction mixtures and reused in subsequent reac-
tions.
With an efficient source for these useful intermediates,
the asymmetric total syntheses of carbocyclic uracil
polyoxin C (+)-2 and its epimer (-)-3 were initiated by
introduction of the 5′-amino acid substituent masked as
the nitroacetate using a stereospecific Pd(0)-mediated
substitution reaction (Scheme 3).14 The inseparable 1:1
mixture of diastereomeric nitroacetates was then reduced
with TiCl3 in the presence of sodium borohydride,12 and
the resulting diastereomeric aminoesters were separated
by chromatography. The intermediate amines were in-
dividually treated with Cbz-chloride and sodium bicar-
13
tion using substoichiometric Mo(CO)6 in the presence
of NaBH4 and development of an efficient kinetic enzy-
matic resolution that provides the desired intermediate
in good yield and in excellent enantiopurity (Scheme 2).
Careful optimization of the reduction step revealed that
treatment of cycloadduct (()-5 with 0.2 equiv of molyb-
denum hexacarbonyl in the presence of excess sodium
borohydride provided aminocyclopentenol (()-7 in 60%
yield from 6. Previously, reduction of (()-5 with 1.1 molar
equiv of Mo(CO)6 required a 2:1 Mo(CO)6/substrate mass
ratio.13a The use of less Mo(CO)6 not only reduced the
toxicity and cost of this synthetic transformation but also
greatly simplified the purification process.
Initial studies have demonstrated that Candida ant-
arctica B lipase accepts an allylic alcohol and provides
(-)-4 in two steps from 5 and in 80% ee.13a Recently, it
(11) Cowart, M.; Bennett, M. J .; Kerwin, J . F., J r. J . Org. Chem.
1999, 64, 2240.
(12) Zhang, D.; Miller, M. J . J . Org. Chem. 1998, 63, 755.
(13) (a) Mulvihill, M. J .; Gage, J . L.; Miller, M. J . J . Org. Chem.
1998, 63, 3357. (b) For an earlier example, 0.7 molar equiv of Mo-
(CO)6 was used alone to do N-O reductive cleavage (without NaBH4).
Cicchi, C.; Goti, A.; Brandi, A.; Guarna, A.; Sarlo, D. F. Tetrahedron
Lett. 1990, 31, 3351.
(14) (a) Trost, B. M. Acc. Chem. Res. 1996, 29, 355. (b) Godleski, S.
A. Nucleophiles with Allyl Metal Complexes. In Comprehensive Organic
Syntheses; Trost, B. M., Ed.; Permagon: Oxford 1991; Vol. 4, Chapter
3.3, pp 585-661. (c) Tsuli, J . Tetrahedron 1986, 42, 4361.
J . Org. Chem, Vol. 69, No. 13, 2004 4539

SCHEME 4
bonate in THF to provide 10a and its R-epimer 10b in a
combined yield of more than 60% for three steps.
using 0.5 N LiOH aqueous solution in methanol, followed
by removal of the benzyl groups by hydrogenolysis over
10% Pd/C to give carbocyclic uracil polyoxin C (+)-2 and
its R-epimer (-)-3 (Scheme 4).
Next, the uracil base was incorporated using a modi-
fication of Shaw and Warrener’s procedure.15 Acid chlo-
ride 11 was prepared by reaction of vinyl ether and oxalyl
chloride with subsequent decarbonylation in 76% yield
after vacuum distillation.16 The N-Boc group of 10a or
10b was removed by exposure to 50% TFA-CH2Cl2, and
the crude TFA salt was washed with saturated aqueous
NaHCO3 solution and extracted by EtOAc. The crude
amine then was treated with acyl isocyanate 12 which
was obtained by refluxing 11 with AgOCN in benzene to
give the intermediate methyl ester 13a or 13b in good
yields. Esters 13a and 13b were refluxed in 1:1 1 N
sulfuric acid solution and methanol to provide uridines
14a and 14b, respectively. Formation of the protected
carbocyclic polyoxin C derivative 15 was accomplished
by dihydroxylation of 14 with catalytic OsO4 and NMO
in THF. Under a variety of conditions,17 the diols 15 and
lactones 16 were obtained in an approximately 1:1 ratio.
The undesired syn-diol spontaneously formed a lactone
as previously reported,12,18 thus simplifying purification
of the desired diol. Final deprotection was then ac-
complished by hydrolysis of methyl esters (15a and 15b)
We have reported an asymmetric synthesis of carbocy-
clic uracil polyoxin C (+)-2 and its R-epimer (-)-3 in an
efficient fashion. The synthesis highlighted a concise,
inexpensive chemoenzymatic synthesis of enantiopure
aminocyclopentenols, a Pd(0)-catalyzed substitution reac-
tion and a mild reduction of an R-nitro ester by TiCl3/
sodium borohydride. These features would allow an
efficient synthesis of all major carbocyclic polyoxin C
analogues in an asymmetric fashion. Significantly, this
synthetic exercise demonstrates new utility for the
versatile enantiopure aminocyclopentenol-based building
blocks.
Ack n ow led gm en t. We gratefully acknowledge the
NIH for support of this research and the Lizzadro
Magnetic Resonance Research Center at Notre Dame
for NMR facilities, as well as Dr. B. Boggess and N.
Sevova for mass spectrometry facilities. We acknowl-
edge Maureen Metcalf for assistance with the manu-
script.
(15) (a) Shaw, G.; Warrener, R. J . Chem. Soc. 1958, 153. (b) Shaw,
G.; Warrener, R. J . Chem. Soc. 1958, 157.
(16) Tietze, L. F.; Schneider, C.; Pretor, M. Synthesis 1993, 11, 1079.
(17) Improving facial selectivity in dihydroxylation reactions with
carbocyclic nucleosides continues to be a synthetic challenge: (a) Trost,
B. M.; Kuo, G. H.; Benneche, T. J . Am. Chem. Soc. 1988, 110, 621. (b)
Ritter, A. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4602. (c) Donohoe,
T. J .; Blades, K.; Helliwell, M.; Moore, P. R.; Winter, J . J . G. J . Org.
Chem. 1999, 64, 2980.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details, compound characterization, and 1H and 13C
NMR spectra for (+)-2, (-)-3, (+)-16a , (+)-16b, (-)-15a , (-)-
15b, (-)-14a , (-) -14b, (-)-10a , (-)-10b. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Aggarwal, V. K.; Monteiro, N. J . Chem. Soc., Perkin Trans. 1
1997, 2531.
J O0496796
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